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PubMed1994

Induction of labor with intravaginal misoprostol in intrauterine fetal death.

OBJECTIVE: Our purpose was to evaluate the effectiveness and safety of intravaginal misoprostol for the induction of labor in intrauterine fetal death. STUDY DESIGN: Seventy-two women at 18 to 40 weeks of pregnancy with intrauterine fetal death, without abdominal scars, were treated with 100 micrograms of intravaginal misoprostol. The dose was repeated every 12 hours until effective uterine contractions and cervical dilatation were obtained, for up to 48 hours. RESULTS: The mean time from induction to delivery was 12.6 hours, and only six patients (8%) required between 24 and 48 hours, at the end of which all patients had been delivered. Only the Bishop's score was significantly associated with time from first dose to expulsion. No surgical procedure was required. Hypercontractility, sweating, fever, diarrhea, or other gastrointestinal effects were not detected. There was no need for analgesics. CONCLUSIONS: Intravaginal misoprostol at the dose of 100 micrograms every 12 hours appears to be a safe, effective, practical, and inexpensive new method for induction of labor in intrauterine fetal death.

Administration, Intravaginal↗
PubMed1993

Induction of labor with intravaginal prostaglandin E2 gel.

OBJECTIVE: The aim of our study was to evaluate the optimum dose of intravaginal prostaglandin E2 gel for induction for labor in nulliparous women with a relatively ripe cervix (modified Bishop score 4 or 5). METHOD: One hundred and sixty-seven nulliparous women at term with indications for the induction of labor were treated randomly with two doses of intravaginal 2.0 (group A) or 3.0 mg (group B) of prostaglandin PGE2 gel every 12 h. Data were analyzed by chi 2-test and Student's t-test. RESULTS: Of 87 patients 64 went into labor after gel application in group A, compared with 68/80 in group B (73.5% vs. 85.0%) (P = NS). A second gel administration was needed for 9 women in group A and 6 women in group B. More side effects (both local and systemic) were noted in group B than in group A (28.7% vs. 14.9%) (P = 0.03). In particular, more local (hyperstimulation or hypertonus) side effects were noted in group B (13.7% vs. 2.3%) (P = 0.01). CONCLUSION: The vaginal administration of 2.0 mg of PGE2 gel seems to be equally effective as 3.0 mg in terms of labor success rate with a significant lower incidence of side effects.

Administration, Intravaginal↗
PubMed1990

The effect of adjuvants on antibody titers in mouse vaginal fluid after intravaginal immunization.

Intravaginal (ivag) immunization elicits secretory immune responses in the female reproductive tract, but little is known about the safety and effectiveness of adjuvants for such immunization. Mice were immunized intravaginally once daily for 5 days with large doses of horse ferritin combined with aluminum hydroxide (AH), muramyl dipeptide (MDP), monophosphoryl lipid A (MPL), dimethyl dioctadecyl ammonium bromide (DDA) or cholera toxin (CT). Titers of anti-ferritin IgA and IgG were measured in vaginal fluid by ELISA. The most effective adjuvant for ivag primary immunization was AH, while MPL was most effective for ivag boosting. None of the adjuvants caused a detectable tissue reaction in vaginal mucosa. Primary ivag immunization for 5 days with ferritin and AH followed by ivag boosting for 5 days with ferritin and MPL elicited higher IgA titers in vaginal fluid than systemic priming and boosting with ferritin and AH or systemic priming and ivag boosting with ferritin and MPL. Systemically immunized animals exhibited the highest IgG titers in vaginal fluid. The data indicate that adjuvants, particularly AH, can increase local immune responses to intravaginal immunization, but it should be noted that multiple applications of large doses of antigen were used and that this route of sensitization may be relatively inefficient.

Adjuvants, Immunologic↗
PubMed1997

Randomized trial of two doses of the prostaglandin E1 analog misoprostol for labor induction.

OBJECTIVE: Our purpose was to compare the safety and effectiveness of intravaginally administered misoprostol at doses of 25 micrograms and 50 micrograms for indicated labor induction in patients with an unfavorable cervix. STUDY DESIGN: Three hundred ninety-nine patients received either 25 micrograms or 50 micrograms of misoprostol, placed intravaginally in the posterior fornix, in this randomized double-blind trial. The dose was repeated every 3 hours until adequate labor was achieved (at least three contractions in 10 minutes). RESULTS: Among 399 patients evaluated, 192 patients were allocated to the 25 micrograms group and 207 patients to the 50 micrograms group. The start-to-delivery interval was shorter in the 50 micrograms group (826 minutes vs 970 minutes, p = 0.02). The incidence of vaginal delivery after one dose was higher in the 50 micrograms group (38.2% vs 25.0%, p = 0.007). Patients receiving 25 micrograms required oxytocin augmentation more frequently than did those receiving 50 micrograms (27.1% vs 16.9%, p = 0.02). No differences were noted in the cesarean or other operative delivery rates among patients in the two treatment groups. The incidence of newborns with a cord pH < 7.16 was greater in the 50 micrograms group (13.0% vs 6.8%, p = 0.04). Although the incidence of hyperstimulation was similar between the groups, the incidence of tachysystole was higher in the 50 micrograms group (32.8% vs 15.6%, p = 0.0001). CONCLUSIONS: Although a dose of 50 micrograms is associated with a shorter start-to-delivery interval and a higher incidence of vaginal delivery after one dose, 25 micrograms of intravaginal misoprostol is effective and associated with a lower incidence of tachysystole and cord pH values < 7.16.

Administration, Intravaginal↗
PubMed1991

Open randomized comparison of prostaglandin E2 given by intracervical gel or vagitory for preinduction cervical ripening and induction of labor.

Intracervical application of prostaglandin E2 (PGE2) in a viscous gel was compared with conventional wax-based PGE2 vagitories (pessaries) for ripening of the cervix prior to induction of labor. A total of 226 healthy pregnant women at term were randomly allocated to receive intracervical gel with an effective dose of 0.5 mg (n = 116) or vagitories containing 2.5 mg PGE2 (n = 110). All women had a modified cervical score of less than or equal to 4. The numbers of cases contributed by each of the three centers were similar. There was no significant difference in parity, gestational length, maternal characteristics, indications for induction or preinduction cervical scores between the treatment groups. The rate of spontaneous birth was 71% in the gel group, compared with 69% in the vagitory group. Successful treatment was defined as active labor within 24 h or a change in cervical dilatation allowing artificial rupture of the membranes with subsequent progressive labor. The success rate was not significantly different in the gel group (82%) compared with the vagitory group (80%). There were no differences in the frequency of fetal distress, outcome of labor, assisted delivery rates or maternal side effects. The cervical scores were not different at 12 and 24 h after application. Intracervical gel and intravaginal application of PGE2 were similar in their efficacy and safety for ripening of the cervix and inducing labor at term.

Administration, Intravaginal↗
PubMed2005

Intravaginal misoprostol versus Foley catheter for cervical ripening and induction of labor.

OBJECTIVE: To compare the efficacy and safety of 100 microg of intravaginal misoprostol with intracervical Foley catheter for cervical ripening and induction of labor. METHOD: One hundred women being induced in the Lagos University Teaching Hospital, Nigeria, were randomized to receive a single 100 microg dose of misoprostol intravaginally or intracervical insertion of Foley catheter. Data analyses were by the Student's t-test and chi-square test. RESULT: Misoprostol was more effective in terms of induction to delivery interval (11.84+/-5.43 versus 20.03+/-4.68 h, P<0.05), change in Bishop score, and number delivered within 24 h, in patients with a one-time successful induction. Uterine hyperactivity and rupture were more frequent in the misoprostol group. CONCLUSION: A single 100 microg dose of intravaginal misoprostol is more efficacious than intracervical insertion of Foley catheter for cervical ripening and induction of labor. Further studies using lower doses are needed to determine the safest dose.

Administration, Intravaginal↗
PubMed2002

Labor induction with 25 microg versus 50 microg intravaginal misoprostol: a systematic review.

OBJECTIVE: To systematically review published randomized controlled trials (RCTs) to compare the safety and efficacy of 25 microg versus 50 microg of intravaginal misoprostol for cervical ripening and labor induction. DATA SOURCES: We supplemented a search of entries in electronic databases with references cited in original studies and review articles to identify RCTs of misoprostol for cervical ripening and labor induction, which compared repeated doses of 25 microg and 50 microg. STUDY SELECTION: We evaluated, abstracted data, and assessed the quality of RCTs to compare the safety and efficacy of 25 microg versus 50 microg of intravaginal misoprostol for cervical ripening and labor induction. TABULATION, INTEGRATION, AND RESULTS: Five RCTs met inclusion criteria for meta-analysis. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for each outcome (random- and fixed-effects models). In addition, we aggregated the results of two separate studies, permitting an indirect comparison of the two doses being analyzed. In the meta-analysis, tachysystole and hyperstimulation syndrome appear to occur less frequently among women who received 25 microg of misoprostol than with 50 microg. However, neonatal outcomes appear to be comparable with the two doses. Regarding efficacy, use of the 50-microg dose was associated with a shorter interval to vaginal delivery, greater proportion of deliveries within 24 hours, and less frequent need for oxytocin augmentation. The indirect comparison of two studies yielded similar results. CONCLUSION: Published data indicate that intravaginal misoprostol at doses of 50 microg for cervical ripening and labor induction is more efficacious but it is unclear whether it is as safe as the 25-microg dose.

Administration, Intravaginal↗
PubMed2001

Is high-dose misoprostol able to lower the incidence of cesarean section? A randomized controlled trial.

OBJECTIVE: To determine whether high-dose (100 microg) misoprostol was able to increase the rate of successful labor induction and lower the incidence of Cesarean section without adverse fetal effects. METHODS: A total of 360 women were randomized to receive either oxytocin (n = 192) by intravenous infusion, or misoprostol (n = 168) 100 microg intravaginally every 4 h. The Cesarean section rate was the primary end-point. Incidences of uterine and fetal heart rate abnormalities during labor and adverse neonatal outcomes were assessed as secondary end-points. RESULTS: Compared with those women receiving oxytocin, patients given misoprostol had a significantly shortened labor (10.7+/-6.0 vs. 15.4+/-10.4 h, p < 0.001). The Cesarean section rate did not differ between patients receiving misoprostol or oxytocin (36 (21.4%) vs. 38 (19.8%), p = 0.79) despite a sample size adequate to detect a 13 percentage point difference in this outcome. Patients receiving misoprostol had a higher incidence of the hyperstimulation syndrome (27 (16.1%) vs. 9 (4.7%), p < 0.001), and of fetal intolerance of labor as an indication for Cesarean delivery (23 (63.9%) vs. 15 (39.5%), p = 0.06), and had a greater number of umbilical artery cord blood pH findings of< 7.20 (20 (43.5%) vs. 6 (17.1%), p = 0.02). These worrisome trends on interim analysis resulted in our prematurely terminating the study. CONCLUSION: High-dose intravaginal misoprostol did not reduce the Cesarean section rate and was associated with a greater hazard of fetal intolerance of labor.

Administration, Intravaginal↗
PubMed1996

Preinduction cervical ripening with intravaginal prostaglandin E1 methyl analogue misoprostol: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of intravaginal prostaglandin E1 methyl analogue misoprostol in cervical ripening in patients with unfavorable cervix (Bishop score < 4) requiring labor induction. METHOD: A randomized controlled clinical trial of 62 women in the third trimester with various indications for induction of labor were randomly allocated to receive either 100 micrograms misoprostol inserted vaginally (32) or placebo similarly applied (30). Transvaginal sonography was performed to measure the cervical length before and 12 hrs after insertion. RESULTS: The mean change in cervical length and Bishop score was significantly greater in the misoprostol group (24 mm and score 8) compared with in the placebo group (2.2 mm and score 1) (p = 0.001). All but one patients receiving misoprostol went into labor while only one in the placebo group did so. The interval from insertion to vaginal delivery was significantly shorter in the misoprostol group (12.0 vs 25.5 hrs, p < 0.001). Delivery occurred within 24 hrs in 75% and 30% of patients in the misoprostol and placebo groups respectively. Uterine tachsystole occurred more frequently in the misoprostol group (38%) than in the placebo group (0%) (p < 0.001). All could be rapidly reversed by tocolytics without apparent untoward intrapartum effects. No significant differences were noted in the 2 groups in terms of perinatal outcomes and mode of delivery. CONCLUSION: Intravaginal misoprostol is an effective, cheap and safe method for cervical ripening. The higher frequency of uterine tachysystole in the misoprostol group did not increase the risk of adverse intrapartum and neonatal outcomes.

Administration, Intravaginal↗
PubMed2003

Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in rabbits.

WHI-05 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate, CAS 213982-93-5) is a highly promising anti-viral and spermicidal agent with clinical potential as a vaginal contraceptive which can prevent the sexual transmission of AIDS. In this study, the contraceptive activity of WHI-05 in rabbits was evaluated. Exposure of semen to WHI-05 at the time of artificial insemination inhibited pregnancy and embryo implantation by 90%. Intravaginal application of 2% WHI-05 containing gel also inhibited the pregnancy rate by 90%. WHI-05 had no side effects for the offspring of rabbits who became pregnant despite WHI-05.

Administration, Intravaginal↗
PubMed1991

[Contraception by cyclic treatment with buserelin and progesterone].

Hormonal contraception with a combination of a GnRH-agonist (Buserelin) and progesterone was achieved in 47 high risk patients in 547 cycles. In these patients, oral contraceptives were contraindicated because of severe cardiovascular diseases, thromboembolic complications, benign liver tumours, advanced diabetes, terminal kidney insufficiency and severe migraine. Buserelin was administered intranasally in one daily dose of 300-400 micrograms from the 1st day to the 21st day, one dose of 100 mg of Progesterone was given intravaginally daily from the 12th day to the 21st day. Under these conditions, average E2 concentrations were found in the range of 50-60 pg/ml. The discontinuation of progesterone replacement resulted in withdrawal bleeding. Cycle control was acceptable. In 4 cases, this contraceptive regimen had to be discontinued because of side effects or paradox reactions. One patient conceived. In conclusion, GnRH-analogues in a moderate dose can be used to inhibit ovulation without inhibiting follicular maturation and adequate oestrogen production. This costly regimen of contraception requires strict indication and careful monitoring.

Administration, Intranasal↗
PubMed2006

The effect of a progesterone releasing intravaginal device (PRID) on pregnancy risk to fixed-time insemination following diagnosis of non-pregnancy in dairy cows.

The objective was to compare the probability of pregnancy after fixed-time insemination in cows diagnosed as non-pregnant and re-inseminated following the Ovsynch protocol, with or without exogenous progesterone. Cows (n=415) used in this study originated from 25 farms. Upon diagnosis of non-pregnancy between 30 and 60 days after AI, cows were randomly assigned to receive either a progesterone releasing intravaginal device (PRID; n=208) or a placebo intravaginal device (PID; n=207). All cows received GnRH at enrollment (Day 0), PGF(2alpha) concurrent with intravaginal device removal 7 days later, GnRH on Day 9 and fixed-time insemination 16h later (Day 10). Cows observed in estrus prior to Day 7, had the device removed and were inseminated. Ovaries were examined by transrectal palpation at the time of enrollment and the prominent structures were assessed and recorded. Body condition score, lameness status, interval from previous insemination, and times bred at enrollment were recorded. At intravaginal device removal, the occurrence and intensity of vaginitis was determined according to the amount of debris on the device. Overall, the intravaginal device retention rate was 91%. A total of 5.2% of PID-treated cows and 2.9% of PRID-treated cows were detected in estrus within the 7 days treatment period. Pregnancy status was diagnosed between 30 and 56 days after insemination and all cows were followed for a minimum of 150 days after enrollment. Approximately 28% of cows had evidence of mild vaginitis in response to the intravaginal device, whereas 6% of cows had copious debris associated with the intravaginal device at removal. The probability of pregnancy after fixed-time insemination was 43.8% versus 34.9% in PRID-treated versus PID-treated animals. Exogenous progesterone provided through an intravaginal device to non-pregnant cows that had not displayed estrus improved the probability of pregnancy after fixed-time AI.

Administration, Intravaginal↗
PubMed2003

A study of the efficacy of cervical ripening with nitric oxide donor versus placebo for cervical priming before second-trimester termination of pregnancy.

This was a double-blind randomized control study to evaluate the efficacy of cervical priming by nitric oxide donor before second-trimester induced abortion. One-hundred healthy women with a singleton pregnancy between 14 and 20 weeks of gestation were randomized into either 40 mg isosorbide mononitrate or placebo, given intravaginally 12 h before induction. This was followed by intravaginal misoprostol induction. The induction-abortion interval, abortion rate, side effects and the woman's acceptability of the priming agent were recorded. All women completed the study and there was no severe complication recorded. There was no significant difference in the induction-abortion interval and abortion rate between the two groups. Isosorbide mononitrate group reported significantly more side effects of headache. More than 90% of the women in both groups found the priming agent acceptable. The application of intravaginal nitric oxide donors prior to the prostaglandins induction did not significantly improve the second-trimester induced-abortion process.

Abortifacient Agents, Steroidal↗
PubMed1999

Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial.

OBJECTIVE: To compare the efficacy and toxicity of topical vaginal 5-fluorouracil (5-FU) maintenance therapy against the effects of observation after standard treatment for high-grade cervical dysplasia in human immunodeficiency virus (HIV)-infected women and to evaluate the association between baseline CD4 count and time to recurrence. METHODS: In a phase III unmasked, randomized, multicenter, outpatient clinical trial, 101 HIV-positive women either received 6 months of biweekly treatment with vaginal 5-FU cream (2 g) or underwent 6 months of observation after standard excisional or ablative cervical treatment for cervical intraepithelial neoplasia (CIN). Papanicolaou smears and colposcopy were scheduled at regular intervals during the ensuing 18 months, with the primary end point being the time at which CIN of any grade recurred. RESULTS: Thirty-eight percent of women developed recurrence: 14 (28%) of 50 in the 5-FU therapy group and 24 (47%) of 51 in the observation group. Treatment with 5-FU was significantly associated with prolonged time to CIN development (P = .04). Observation subjects were more likely to have high-grade recurrences, with 31% developing CIN 2-3 compared with 8% in the 5-FU treatment arm (P = .014), and disease recurred more quickly in observation subjects as well. Baseline CD4 count was related significantly to time to recurrence (P = .04), with 46% of subjects with CD4 counts less than 200 cells/mm3 developing recurrence compared with 33% of subjects with CD4 counts at least 200 cells/mm3. Disease recurred more slowly in subjects who had received antiretroviral therapy than in antiretroviral therapy-naive subjects. There were no instances of grade 3 or 4 toxicity, and compliance with 5-FU treatment was generally good. CONCLUSION: Adjunctive maintenance intravaginal 5-FU therapy after standard surgery for high-grade lesions safely and effectively reduced recurrence of cervical intraepithelial neoplasia in HIV-infected women.

Administration, Intravaginal↗
PubMedDate not supplied

Induction of labor: the misoprostol controversy.

Misoprostol (Cytotec) is safe and effective for induction of labor, although it is not approved by the Food and Drug Administration (FDA) for use in pregnancy. In August 2000, the manufacturer of misoprostol warned against its use in pregnancy because of its abortifacient properties and cited reports of maternal and fetal deaths when misoprostol was used to induce labor, fueling the misoprostol controversy. More than 45 randomized trials including more than 5400 women have found vaginal misoprostol to be more effective than oxytocin or vaginal prostaglandin E2 at effecting vaginal delivery within 24 hours. Cesarean delivery rates with vaginal misoprostol are lower than with oxytocin alone, but similar to prostaglandin E2. There have been no significant differences in the frequency of serious adverse maternal or neonatal outcomes with low-dose misoprostol compared with oxytocin or prostaglandin E2; however, the relative risk of rare adverse outcomes with misoprostol is unknown. The data suggest that absolute risks are low when misoprostol is used appropriately. We recommend 25 mcg vaginally every 4 to 6 hours for carefully selected patients in closely monitored settings. Whether misoprostol will prove to be the most cost-effective agent for inducing labor in women with an unfavorable cervix remains to be determined.

Administration, Intravaginal↗
PubMed1987

[Differentiation of an outcome sample in elective labor induction with PGE2 by the oxytocin sensitivity test].

The goal of the present study was to evaluate whether the implementation of an oxytocin sensitivity test in addition to pelvic scoring would improve prediction of successful induction and could lead to a further reduction in the already low rate of protracted labour and operative deliveries in cases of elective induction by means of prostaglandin (PG) E2 tablets. In order to establish the optimal dosage we compared the endocervical application of 1.5 mg PG E2 with 3 mg intravaginally. Out of 158 women without risk factors examined at term 73.5% decided to have labour induced. In the induction groups given endocervical or intravaginal PG E2 the delivery intervals were significantly shorter and the rate of operative deliveries was reduced. In comparison with those women who decided to await spontaneous onset of labour, the fetal outcome was, however, the same. The endocervical application of 1.5 mg PG E2 did not prove any better than 3 mg given intravaginally. The performance of a pretherapeutic oxytocin sensitivity test yielded additional information about the chances of inducing labour successfully. The results confirmed the efficacy and acceptance of this method of inducing labour.

Administration, Intravaginal↗
PubMed2006

A polyherbal vaginal pessary with spermicidal and antimicrobial action: evaluation of its safety.

A polyherbal vaginal pessary (Praneem) has been formulated that has antimicrobial properties against genital pathogens in addition to spermicidal action. Thus, it has dual potential as a barrier method for contraception and for providing protection against some sexually transmitted infections. The present study reports the findings of a multicentre trial that was conducted to evaluate the safety of this product. Trials were carried out in 23 women in three centres in India: the Postgraduate Institute of Medical Education and Research, Chandigarh; Safdarjang Hospital, New Delhi; and Kamla Nehru Memorial Hospital, Allahabad. Thorough clinical and pelvic examinations were carried out as well as cervical cytology, blood biochemistry and haematology before and after use of the polyherbal pessary intravaginally once daily for 7 consecutive days. No toxicity was observed on clinical examination or by laboratory investigations. Daily intravaginal use of this pessary for 7 days had no adverse effects on cervical cytology or on metabolic and organ functions.

Administration, Intravaginal↗
PubMed2003

A randomized controlled trial of outpatient versus inpatient labour induction with vaginal controlled-release prostaglandin-E2: effectiveness and satisfaction.

BACKGROUND: Outpatient management in obstetrics is expanding, but evidence to support outpatient labour induction is needed. OBJECTIVE: To compare the effectiveness, acceptability, duration of hospitalization, and safety of outpatient and inpatient induction of labour with intravaginal controlled-release prosta-glandin-E2 (CR-PGE2). METHODS: A prospective, randomized, controlled trial enrolled 300 women at term with parity < or = 5 and singleton pregnancies in cephalic presentation. Each had an unscarred uterus, a normal non-stress test (NST), and a Bishop score of < or = 6. After insertion of the CR-PGE2, and 1 hour of monitoring, those in the outpatient group were discharged home, to return with onset of labour or 12 hours later for an NST. If not already in labour 24 hours later, the women returned for inpatient induction. Vaginal examination was not repeated before 24 hours unless the patient was contracting and required analgesia. Inpatients remained on the antepartum ward but were otherwise treated similarly. The women in both groups reported ratings of satisfaction, pain, and anxiety over the telephone until they were in labour. RESULTS: There were 150 women randomized to outpatient and 150 women to inpatient induction of labour. The number of women who were in labour or who delivered by 24 hours in the outpatient group was 115 (0.77, 95% confidence interval [CI] 0.70-0.84) and in the inpatient group was 107 (0.72, 95% CI 0.64-0.79). The median times to labour were 9.8 hours (95% CI, 8.1-11.4) and 11.4 hours (95% CI, 10.1-12.7), and to delivery were 21.4 hours (95% CI, 19.2-23.5) and 20.7 hours (95% CI, 18.4-23.0), for the outpatient and inpatient groups, respectively. In the outpatient group, 56% of women reported high satisfaction during the initial 12 hours of induction compared to 39% in the inpatient group (p < 0.008). Ratings of pain and anxiety during the first 12 hours of induction were similar. In the outpatient group, women were at home for a median of 8 hours (95% CI, 6.7-9.4) before labour and delivery. There were no significant differences in adverse outcomes. CONCLUSIONS: This study suggests that outpatient induction of labour with intravaginal CR-PGE2 may be a reasonable option for selected low-risk women; however, further study is needed to confirm the safety of this approach.

Administration, Intravaginal↗